Macrophage-expressed IFN-β Contributes to Apoptotic Alveolar Epithelial Cell Injury in Severe Influenza Virus Pneumonia

Abstract

Influenza viruses (IV) cause pneumonia in humans with progression to lung failure and fatal outcome. Dysregulated release of cytokines including type I interferons (IFNs) has been attributed a crucial role in immune-mediated pulmonary injury during severe IV infection. Using ex vivo and in vivo IV infection models, we demonstrate that alveolar macrophage (AM)-expressed IFN-β significantly contributes to IV-induced alveolar epithelial cell (AEC) injury by autocrine induction of the pro-apoptotic factor TNF-related apoptosis-inducing ligand (TRAIL). Of note, TRAIL was highly upregulated in and released from AM of patients with pandemic H1N1 IV-induced acute lung injury. Elucidating the cell-specific underlying signalling pathways revealed that IV infection induced IFN-β release in AM in a protein kinase R- (PKR-) and NF-κB-dependent way. Bone marrow chimeric mice lacking these signalling mediators in resident and lung-recruited AM and mice subjected to alveolar neutralization of IFN-β and TRAIL displayed reduced alveolar epithelial cell apoptosis and attenuated lung injury during severe IV pneumonia. Together, we demonstrate that macrophage-released type I IFNs, apart from their well-known anti-viral properties, contribute to IV-induced AEC damage and lung injury by autocrine induction of the pro-apoptotic factor TRAIL. Our data suggest that therapeutic targeting of the macrophage IFN-β-TRAIL axis might represent a promising strategy to attenuate IV-induced acute lung injury.

TLR and RLR Signaling Are Reprogrammed in Opposite Directions after Detection of Viral Infection

“…However, type I IFN production can be maintained through specialized pDCs by the increased sensitivity of endosomal TLRs. Additionally, excessive or prolonged type I IFN release and RLR stimulation can have immunopathological (38)(39)(40)(41) or immunosuppressive (42,43) effects, underscoring the need for tight control of this cytokine. Interestingly, type I IFN was also shown to interfere with the induction of IL-12 and IFN-g (44).…”

Influenza virus-induced lung injury: pathogenesis and implications for treatment

“…For example, in response to IAV, the pro-apoptotic cytokine TNF-related apoptosis-inducing ligand (TRAIL) is strongly expressed on monocyte-derived alveolar macrophages in mice and in bronchoalveolar lavage macrophages from patients with pandemic H1N1 influenza-induced ARDS [107]. TRAIL can directly induce alveolar epithelial cell apoptosis by interacting with death receptor 5, which is highly expressed in the lung epithelium at baseline and is upregulated by type I IFNs during viral infection [107,108]. Strategies that prevent TRAIL-induced apoptosis attenuate the severity of IAV pneumonia in mice without compromising viral load [107,108], whereas those that promote it worsen injury [109].…”

“…TRAIL can directly induce alveolar epithelial cell apoptosis by interacting with death receptor 5, which is highly expressed in the lung epithelium at baseline and is upregulated by type I IFNs during viral infection [107,108]. Strategies that prevent TRAIL-induced apoptosis attenuate the severity of IAV pneumonia in mice without compromising viral load [107,108], whereas those that promote it worsen injury [109].…”

Influenza virus replication in macrophages: balancing protection and pathogenesis

“…Inflammatory cytokines produced by macrophages during IAV infection are important for virus clearance [8,14,17]. However, an exaggerated inflammatory response is believed to contribute to H5N1-associated morbidity and mortality [52][53][54][55].…”

“…On the other hand, macrophages have been implicated in the pathogenesis of severe IAV disease. Excessive pulmonary infiltration of macrophages secreting enhanced levels of pro-inflammatory cytokines is a hallmark of IAVinduced severe pneumonia [14][15][16][17]. Recently, efforts to understand the role of macrophages in IAV pathogenesis have focused on whether influenza viruses have the ability to replicate productively in macrophages.…”